The studies proposed here are designed to elucidate the functions of noradrenergic (NA) and serotonergic (S) afferents in primate neocortex. These projections originate in brainstem nuclei (the locus ceruleus (LC) and raphe nuclei (R), respectively) and innervate the entire neocortical mantle. Our immunohistochemical studies indicate that both systems innervate monkey neocortex more densely than previously thought, with each exhibiting a unique pattern of specialization in terms of region-specific densities and laminar distributions of fibers. This suggests differing functions for the two transmitters in terms of the cytoarchitectonic regions and the classes of neurons which are their principal targets. We have described enhanced acoustic signal processing by monkey auditory cortex neurons during microiontophoresis of NA. These and other observations suggest an important role for NA input in modulating spontaneous and stimulus-elicited neocortical neuronal activity. Other data suggest that the physiologic functions of S innervation differ from those of NA innervation. To demonstrate specific functions for these systems in neocortex, multiple coordinated experiments are proposed. Microiontophoresis, manipulation of source-cell activity, and transmitter-specific lesions will be combined with single-cell recording from neocortical sensory regions to determine the impact of each system on cortical neuronal responses in unanesthetized monkeys. Histological reconstruction of recording sites will include immunohistochemical visualization of NA and S fibers to permit direct comparison of the distribution of their effects on cortical neuronal activity with the regional and laminar distribution of their axons. Our previous data describing the activity of monkey LC neurons and the conduction properties of their axons will be used to make experiments on the LC-NA system as physiologically relevant as possible. Experiments to determine the discharge characteristics and axonal conduction properties of primate R neurons are also proposed. These studies will yield: 1) detailed maps of NA and S innervation of specific cortical fields, 2) quantified measurements of the effects of iontophoretically applied S, NA and other putative neurotransmitters on functionally characterized neocortical neuronal activity, 3) comparable data on LC and R activation and lesion effects, 4) correlation between LC or R and neocortical neuronal activity, 5) hypotheses of the roles of these systems in neocortical information processing.